Retinoic acid dampens LPS-induced NF-kappaB activity: results from human monoblasts and in vivo imaging of NF-kappaB reporter mice.
Bacterial lipopolysaccharide (LPS) is a major inducer of systemic inflammatory reactions and oxidative stress in response to microbial infections and may cause sepsis. In the present study, we demonstrate that retinoic acid inhibits LPS-induced activation in transgenic reporter mice and human monoblasts through inhibition of nuclear factor kappaB (NF-kappaB). By using noninvasive molecular imaging of NF-kappaB luciferase reporter mice, we showed that administration of retinoic acid repressed LPS-induced whole-body luminescence, demonstrating in vivo the dynamics of retinoic acid's ability to repress physiologic response to LPS. Retinoic acid also inhibited LPS-induced NF-kappaB activity in the human myeloblastic cell line U937. Retinoic-acid-receptor-selective agonists mimicked - while specific antagonists inhibited - the effects of retinoic acid, suggesting the involvement of nuclear retinoic acid receptors. Retinoic acid also repressed LPS-induced transcription of NF-kappaB target genes such as IL-6, MCP-1 and COX-2. The effect of retinoic acid was dependent on new protein synthesis, was obstructed by a deacetylase inhibitor and was partly eliminated by a signal transducer and activator of transcription-1 (STAT1)/methyltransferase inhibitor, indicating that retinoic acid induces a new protein, possibly STAT1, that is involved in inhibiting NF-kappaB. This provides more evidence for retinoic acid's anti-inflammatory potential, which may have clinical implications in terms of fighting microbial infections.
Austenaa
Liv M
LM
Department of Nutrition Research, Institute of Basic Medical Sciences, University of Oslo, Norway.
Carlsen
Harald
H
Hollung
Kristin
K
Blomhoff
Heidi K
HK
Blomhoff
Rune
R
D000704:Analysis of Variance; D000818:Animals; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D017930:Genes, Reporter; D006801:Humans; D007279:Injections, Subcutaneous; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology*; D008156:Luciferases; D008163:Luminescent Measurements; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D055017:Monocyte-Macrophage Precursor Cells / Q000276:immunology / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D011993:Recombinant Fusion Proteins; D050794:STAT1 Transcription Factor / Q000819:agonists / Q000378:metabolism; D018709:Statistics, Nonparametric; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D014212:Tretinoin / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D020298:U937 Cells; D051598:Whole Body Imaging
D018932:Chemokine CCL2; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D050794:STAT1 Transcription Factor; D051996:Transcription Factor RelA; D014212:Tretinoin; D008156:Luciferases; D051546:Cyclooxygenase 2